1. Field of the Invention
The current invention provides compounds, compositions and methods to modulate organ and tissue transplant rejection and prolong the survival of transplanted organs and tissues.
2. Background Art
Organ and tissue transplantation has become a standard surgical procedure. In 1990, 15,000 organ transplantations were performed, and by 1999, this number was up to 21,000. The success of surgical transplantation of organs and tissue is largely dependent on the ability of the clinician to modulate the immune response of the transplant recipient. Specifically the immunological response directed against the transplanted foreign tissue must be controlled if the tissue is to survive and function. Currently, skin, kidney, liver, pancreas, lung and heart are the major organs or tissues with which allogeneic transplantations are performed. It has long been known that the normally functioning immune system of the transplant recipient recognizes the transplanted organ as xe2x80x9cnon-selfxe2x80x9d tissue and thereafter mounts an immune response to the presence of the transplanted organ. Left unchecked, the immune response will generate a plurality of cells and proteins that will ultimately result in the loss of biological functioning or the death of the transplanted organ.
This tissue/organ rejection can be categorized into three types: hyperacute, acute and chronic. Hyperacute rejection is essentially caused by circulating antibodies in the blood that are directed against the tissue of the transplanted organ (transplant). Hyperacute rejection can occur in a very short timexe2x80x94often in minutesxe2x80x94and leads to necrosis of the transplant. Acute graft rejection reaction is also immunologically mediated and somewhat delayed compared to hyperacute rejection. The chronic form of graft rejection that can occur years after the transplant is the result of a disease state commonly referred to as Graft Arterial Disease (GAD). GAD is largely a vascular disease characterized by neointimal proliferation of smooth muscle cells and mononuclear infiltrates in large and small vessels. This neointimal growth can lead to vessel fibrosis and occlusion, lessening blood flow to the graft tissue and resulting in organ failure. Current immunosuppressant therapies do not adequately prevent chronic rejection. Most of the gains in survival in the last decade are due to improvements in immunosuppressive drugs that prevent acute rejection. However, chronic rejection losses remain the same and drugs that can prevent it are a critical unmet medical need.
It is additionally known that the transplant-host relationship is not restricted to rejection by the host organism alone; in certain cases an immune reaction originating from the transplant and directed against the host tissue (Graft versus Host Disease (GVHD)) can occur (EP-A-217,206). A differentiation is therefore made between a rejection between transplant and host and between host and transplant.
Tissue and organ transplant recipients are customarily treated with one or more cytotoxic agents in an effort to suppress the transplant recipient""s immune response against the transplanted organ or tissue. Current immunosuppressant drugs include: cyclosporin, tacrolimus (FK506), sirolimus (rapamycin), methotrexate, mycophenolic acid (mycophenolate mofetil), everolimus, azathiprine, steroids and NOX-100. All of these drugs have side effects (detailed below) that complicate their long-term use. For example, cyclosporin (cyclosporin A), a cyclic polypeptide consisting of 11 amino acid residues and produced by the fungus species Tolypocladium inflatum Gams, is currently the drug of choice for administration to the recipients of allogeneic kidney, liver, pancreas and heart (i.e., wherein donor and recipient are of the same species of mammals) transplants. However, administration of cyclosporin is not without drawbacks as the drug can cause kidney and liver toxicity as well as hypertension. Moreover, use of cyclosporin can lead to malignancies (such as lymphoma) as well as opportunistic infection due to the xe2x80x9cglobalxe2x80x9d nature of the immunosuppression it induces in patients receiving long term treatment with the drug, i.e., the hosts normal protective immune response to pathogenic microorganisms is downregulated thereby increasing the risk of infections caused by these agents.
FK506 (tacrolimus) has also been employed as an immunosuppressive agent as a stand-alone treatment or in combination. Although its immunosuppressive activity is 10-100 times greater than cyclosporin, it still has toxicity issues. Known side effects include kidney damage, seizures, tremors, high blood pressure, diabetes, high blood potassium, headache, insomnia, confusion, seizures, neuropathy, and gout. It has also been associated with miscarriages.
Methotrexate is commonly added to the treatment of the cytotoxic agent. Methotrexate is given in small doses several times after the transplant. Although the combination of cyclosporin and methotrexate has been found to be effective in decreasing the severity of transplant rejection, there are side effects, such as mouth sores and liver damage.
Severe transplant rejection can be treated with steroids. However, the side effects of steroids can be extreme, such as weight gain, fluid retention, elevated blood sugar, mood swings, and/or confused thinking.
Rapamycin, a lipophilic macrolide used as an anti-rejection medication can be taken in conjunction with other anti-rejection medicines (i.e., cyclosporin) to reduce the amount of toxicity of the primary cytotoxic agent, but it too has specific side effects, such as causing high cholesterol, high triglycerides, high blood pressure, rash and acne. Moreover, it has been associated with anemia, joint pain, diarrhea, low potassium and a decrease in blood platelets.
Vitamin D has been employed to decrease bone loss caused by cyclosporin (U.S. Pat. No. 6,071,897) and was shown to decrease the possibility of infection noted by the use of cyclosporin.
Although many approaches have been conceived to treat transplant rejection, there is still room for improvement. (See U.S. Pat. Nos. 6,239,124, 6,071,897, 5,788,968, 5,728,721, 5,308,847, 5,298,523, 5,212,155, 5,100,899 all herein incorporated by reference in their entirety.)
U.S. Pat. No. 5,262,439 to Parthasarathy, which is assigned to AtheroGenics, Inc. discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. In one embodiment, the derivative is selected from the group consisting of a mono- or di-probucol ester of succinic acid, glutaric acid, adipic acid, seberic acid, sebacic acid, azelaic acid, or maleic acid. In another embodiment, the probucol derivative is a mono- or di-ester in which the ester contains an alkyl or alkenyl group that contains a functionality selected from the group consisting of a carboxylic acid group, amine group, salt of an amine group, amide groups, amide groups, and aldehyde groups.
U.S. Pat. No. 6,121,319, which issued on Sep. 19, 2000, and corresponding WO 98/51662 filed by AtheroGenics, Inc. and published on Nov. 18, 1998, describes certain compounds of formula having the structure 
wherein:
Ra, Rb, Rc, and Rd are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the Ra, Rb, Rc and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, xe2x80x94(CH2)xe2x80x94Re, xe2x80x94C(O)xe2x80x94Rg, and xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Rh, wherein (a) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be hydrogen; and
the other variables are as defined in those specifications, for the treatment of disorders mediated by VCAM-1, and inflammatory and cardiovascular disorders.
WO 01/70757 filed by AtheroGenics, Inc. and published on Sep. 27, 2001, describes the use of certain thioethers of the following formula, and pharmaceutically acceptable salts thereof: 
wherein
a) Ra, Rb, Rc, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and
b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C1-10alkyl or substituted C1-10alkyl, terminated by sulfonic acid, (iv) C1-10alkyl or substituted C1-10alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C1-10alkylxe2x80x94Oxe2x80x94C(O)xe2x80x94C1-10alkyl, (vi) straight chained polyhydroxylated C3-10alkyl; (vii)xe2x80x94(CR2)1-6xe2x80x94COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) xe2x80x94(CR2)1-6xe2x80x94X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
for use in treating organ transplant rejection.
Given the strong side effects of the current drugs, typically immunosuppressant drugs, that are now commonly used in treating solid organ transplant rejection, there is a strong need to provide new methods in the tissue and transplant field that have low toxicity and are effective in transplant rejection either alone or in combination with known treatment regimens.
The present invention provides a method of inhibiting organ or tissue transplant rejection in a mammal, either alone or in combination with other medications, wherein the method comprises administering a compound of the formula 
or a pharmaceutically acceptable salt thereof wherein:
Y is a bond or 
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, hydroxy, C1-10alkyl, aryl, heteroaryl, C1-10alkaryl, and aryl C1-10alkyl, wherein all nonhydrogen and hydroxy substituents may optionally be substituted from one or more of the group selected from C1-10alkyl, halogen, nitro, amino, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, heterocyclC1-10alkyl, R7NH, R7R7N, carboxy, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R5;
R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)Oxe2x80x94R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8; and
R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
wherein two R7 groups may come together to form a 4 to 7 membered ring.
The present invention also provides a method of moderating transplant rejection and a method to increase transplant survival. Other advantages of the invention will become clearer in light of the detailed description, drawings and claims.
This method can be used to treat tissue/organ rejection categorized as either or a combination of hyperacute, acute and chronic. The invention is particularly useful in treating the chronic form of organ rejection, and in particular Graft Arterial Disease. The method can be used to treat rejection of any organ, and in particular, skin, kidney, liver, pancreas, lung and heart.
The invention also includes pharmaceutical compositions suitable for the treatment of transplant rejection.